Taysha Gene Therapies Inc (TSHA) 2025 Q3 法說會逐字稿

Good day, everyone and welcome to the Taysha Gene Therapies third quarter 2025 earnings call. (Operator Instructions) Please note, this call may be recorded, and I will be standing by if you should need any assistance.

大家好，歡迎參加 Taysha Gene Therapies 2025 年第三季財報電話會議。（操作員說明）請注意，本次通話可能會被錄音，如果您需要任何協助，我將隨時為您提供服務。

It is now my pleasure to turn the conference over to Hayleigh Collins. Please go ahead.

現在我很高興將會議交給海莉柯林斯主持。請繼續。

Thank you. Good morning and welcome to our third quarter 2025 financial results and corporate update call. Earlier today, Taysha issued a press release announcing financial results for the third quarter ended September 30, 2025. A copy of this press release is available on the company's website and through our SEC filings. Joining me on today's call are Sean Nolan, Taysha's Chief Executive Officer; Sukumar Nagendran, President and Head of R&D; and Kamran Alam, Chief Financial Officer.

謝謝。早安，歡迎參加我們2025年第三季財務業績及公司最新進展電話會議。今天早些時候，泰莎發布新聞稿，公佈了截至 2025 年 9 月 30 日的第三季財務業績。本新聞稿的副本可在公司網站和我們向美國證券交易委員會提交的文件中找到。今天與我一起參加電話會議的有：Taysha 執行長 Sean Nolan；總裁兼研發主管 Sukumar Nagendran；以及財務長 Kamran Alam。

We will hold a question-and-answer session following our prepared remarks. On today's call, we will be making forward-looking statements, including statements concerning the potential of TSHA-102, including the reproducibility and durability of any favorable results initially seen in patients dosed to date in clinical trials, including with respect to functional milestones, to positively impact quality of life and alter the course of disease in the patients we seek to treat; our research, development, and regulatory plans for our product candidates, including the timing of initiating additional trials, reporting data from our clinical trials, and making regulatory submissions; timing or outcomes of communications with the FDA on the regulatory pathway for TSHA-102; the potential for the product candidate to receive regulatory approval from the FDA or equivalent regulatory agencies; our ability to realize the benefits of Breakthrough Therapy designation for TSHA-102; and the market opportunity for our programs.

我們將在發言結束後進行問答環節。在今天的電話會議上，我們將發表前瞻性聲明，包括有關 TSHA-102 潛力的聲明，例如迄今為止在臨床試驗中接受給藥的患者中觀察到的任何有利結果的可重複性和持久性，包括功能性里程碑，以積極影響我們旨在治療的患者的生活質量並改變疾病進程；我們針對候選產品的研發和監管計劃，包括啟動其他數據和監管臨床數據監管途徑進行溝通的時間或結果；該候選產品獲得 FDA 或同等監管機構批准的可能性；我們實現 TSHA-102 突破性療法認定益處的能力；以及我們項目的市場機會。

This call may also contain forward-looking statements relating to Taysha's growth, forecasted cash runway, and future operating results; discovery and development of product candidates, strategic alliances, and intellectual property; as well as matters that are not historical facts or information. Various risks may cause Taysha's actual results to differ materially from those stated or implied in such forward-looking statements. For a list and description of the risks and uncertainties that we face, please see the reports that we have filed with the SEC, including in our annual report on Form 10-K for the full year December 31, 2024, that we filed February 26, 2025, and our quarterly report on Form 10-Q for the quarter ended September 30, 2025, that we filed today.

本次電話會議可能包含有關 Taysha 的成長、預期現金流量和未來營運績效；產品候選藥物的發現和開發、策略聯盟和智慧財產權；以及非歷史事實或資訊的前瞻性陳述。各種風險可能導致 Taysha 的實際表現與此類前瞻性聲明中明示或暗示的績效有重大差異。有關我們面臨的風險和不確定性的清單和說明，請參閱我們向美國證券交易委員會提交的報告，包括我們於 2025 年 2 月 26 日提交的截至 2024 年 12 月 31 日的年度 10-K 表格報告，以及我們今天提交的截至 2025 年 9 月 30 日的季度表格 10-Q 表格。

This conference call contains time-sensitive information that is accurate only as of the date of this live broadcast, November 4, 2025. Taysha undertakes no obligation to revise or update any forward-looking statements to reflect events or circumstances after the date of this conference call, except as may be required by applicable securities laws.

本次電話會議包含時效性訊息，僅在本次直播當天（2025 年 11 月 4 日）有效。除適用證券法可能要求的情況外，Taysha 不承擔任何義務修改或更新任何前瞻性聲明以反映本次電話會議日期之後的事件或情況。

With that, I would now like to turn the call over to our CEO, Sean Nolan.

接下來，我想把電話交給我們的執行長肖恩諾蘭。

Thank you, Haley, and welcome everyone to our third-quarter conference call. I will begin with an update of our recent corporate activities and progress across our TSHA-102 Rett syndrome program. Suku will then discuss the new supplemental analysis from Part A of our REVEAL Phase 1/2 trials. Kamran will follow up with a financial update, and I will provide closing remarks before opening the call to questions.

謝謝 Haley，歡迎各位參加我們第三季電話會議。首先，我將介紹我們最近的公司活動以及我們在 TSHA-102 Rett 綜合徵專案方面取得的進展。接下來，Suku 將討論我們 REVEAL 1/2 期試驗 A 部分的最新補充分析。Kamran 將隨後報告財務最新情況，我將作總結發言，之後將開放提問環節。

In the quarter, we believe we made meaningful progress that sets the stage for what could be a transformative period ahead for Taysha. The recent regulatory clarity and progress we've achieved, which was enabled by the strength of our REVEAL Part A data set, rigorous data evaluation methodology, and our natural history data analysis allows us to focus on executing our REVEAL pivotal trial and advancing towards BLA submission with clarity and confidence.

我們相信，本季我們取得了有意義的進展，為泰莎未來可能迎來的變革時期奠定了基礎。憑藉我們強大的 REVEAL A 部分數據集、嚴格的數據評估方法和自然史數據分析，我們最近在監管方面取得了清晰的進展，這使我們能夠專注於執行 REVEAL 關鍵性試驗，並清晰、自信地推進 BLA 的提交。

A major milestone was the receipt of FDA Breakthrough Therapy designation for TSHA-102 at the end of September. This designation is designed to expedite the development and review of therapies for serious conditions that have demonstrated preliminary clinical evidence of substantial improvement over available treatments in one or more clinically meaningful endpoints. TSHA-102 received Breakthrough Therapy designation based on the FDA's review of available safety and efficacy data from all 12 pediatric, adolescent, and adult patients treated with TSHA-102 in Part A of our REVEAL Phase 1/2 trials, including clinical data from the previously disclosed May 2025 data cutoff. Receiving Breakthrough designation highlights the FDA's recognition of both the significant unmet medical need among the 10,000 patients suffering from Rett syndrome in the US and the therapeutic potential of TSHA-102 to redefine the treatment paradigm for this devastating disease.

一個重要的里程碑是，TSHA-102 在 9 月底獲得了 FDA 突破性療法認定。該認定旨在加快針對嚴重疾病的療法的開發和審查，這些療法已初步證明在一個或多個具有臨床意義的終點方面比現有療法有顯著改善。根據 FDA 對我們 REVEAL 1/2 期試驗 A 部分中接受 TSHA-102 治療的所有 12 名兒科、青少年和成人患者的現有安全性和有效性數據的審查，TSHA-102 獲得了突破性療法認定，其中包括此前披露的 2025 年 5 月數據截止日期的臨床數據。獲得突破性療法認定，凸顯了 FDA 對美國 10,000 名雷特氏症患者中未滿足的重大醫療需求以及 TSHA-102 治療潛力的認可，後者有望重新定義這種毀滅性疾病的治療模式。

Notably, over 80% of programs with Breakthrough Therapy designation that proceeded to file for approval have ultimately received FDA approval. We look forward to continued engagement with the FDA as we advance toward potential registration.

值得注意的是，超過 80% 獲得突破性療法認定並提交審批申請的計畫最終都獲得了 FDA 的批准。我們期待在推進潛在註冊的過程中繼續與FDA保持溝通。

In September, we finalized alignment with FDA on our REVEAL pivotal trial protocol and statistical analysis plan in support of our planned BLA submission for TSHA-102, following resolution of remaining clinical and statistical queries. Importantly, our previously aligned-upon key design elements remain unchanged. In line with FDA's guidance for cell and gene therapy programs that was issued in September, we believe that the prospectively aligned by -- that by prospectively aligning with FDA on the statistical analysis plan for our pivotal trial helps ensure that the data set collected will be considered reliable and suitable for BLA submission.

9 月，在解決了剩餘的臨床和統計問題後，我們與 FDA 就 REVEAL 關鍵性試驗方案和統計分析計劃達成一致，以支持我們計劃向 TSHA-102 提交的 BLA 申請。重要的是，我們先前確定的關鍵設計要素保持不變。根據 FDA 於 9 月發布的細胞和基因治療項目指南，我們相信，透過與 FDA 就我們關鍵性試驗的統計分析計劃進行前瞻性協調，有助於確保收集到的數據集將被認為是可靠的，並適合提交 BLA。

We are enrolling 15 patients in the developmental plateau population of Rett syndrome with a primary endpoint of response rate which is defined as the percentage of patients who gain or regain one or more of the 28 natural history defined developmental milestones. A response rate of 33%, equivalent to 5 out of 15 patients, is the minimum threshold for success sufficient to achieve our primary endpoint. Notably, we've observed a 100% response rate across the 10 patients in Part A of our REVEAL trials. Additionally, we aligned with the FDA on a six-month interim analysis that may serve as the basis for BLA submission, potentially accelerating our planned BLA submission by at least two quarters.

我們正在招募 15 名處於 Rett 症候群發育平台期的患者，主要終點是反應率，定義為獲得或恢復 28 個自然病程定義的發育里程碑中的一個或多個的患者百分比。33% 的回應率（相當於 15 名患者中有 5 名回應）是達到我們主要終點所需的最低成功閾值。值得注意的是，我們在 REVEAL 試驗 A 部分的 10 名患者中觀察到了 100% 的回應率。此外，我們與 FDA 達成一致，進行了一項為期六個月的中期分析，該分析可作為生物製品許可申請 (BLA) 的基礎，有可能將我們計劃的 BLA 提交時間至少提前兩個季度。

As previously disclosed, the data from Part A of the REVEAL trials demonstrated an 83% response rate at 6 months post treatment, with five of the six patients treated with the high-dose TSHA-102 achieving a developmental milestone. We observed a consistent pattern of sustained milestone gains with a deepening of effect or additional milestone gains over time. By nine months post treatment, the data demonstrated a 100% response rate across the six treated high-dose patients in Part A. We believe these data support both the suitability of the six-month time point to demonstrate clinically meaningful efficacy and that the six-month efficacy data may be representative of treatment effects at 12 months. We believe this enabled our alignment with FDA that a six-month interim analysis may serve as the basis for BLA submission.

如先前揭露的那樣，REVEAL 試驗 A 部分的數據顯示，治療後 6 個月的反應率為 83%，接受高劑量 TSHA-102 治療的 6 名患者中有 5 名達到了發展里程碑。我們觀察到，里程碑式的持續進展呈現一致的模式，隨著時間的推移，效果會加深，或會取得額外的里程碑式進展。治療後九個月，數據顯示 A 部分接受高劑量治療的六名患者的回應率為 100%。我們認為這些數據支持六個月時間點適合證明具有臨床意義的療效，而六個月的療效數據可能代表 12 個月時的治療效果。我們相信，這使我們能夠與 FDA 達成一致，即六個月的中期分析可以作為生物製品許可申請 (BLA) 的基礎。

It's important to understand that we believe we received Breakthrough Therapy designation and achieved FDA alignment largely due to the results of the rigorous clinical evaluation methodology applied to our video-evidenced developmental milestone data from Part A of the REVEAL Phase 1/2 trials.

重要的是要理解，我們相信我們之所以獲得突破性療法認定並獲得 FDA 的認可，主要是因為我們對 REVEAL 1/2 期試驗 A 部分的視頻證據發育里程碑數據應用了嚴格的臨床評估方法。

In Part A, videos were centrally rated by multiple independent reviewers using milestone definitions from the pivotal trial protocol to ensure an objective, consistent evaluation of milestone gain and regain in the developmental plateau population where these gains are not expected to spontaneously occur. By adhering to rigorous milestone evaluation criteria based on natural history, this approach minimizes bias and avoids overcounting milestones by ensuring the milestones are truly eligible for gain or regain. As a result, this provides a reliable reflection of TSHA-102's disease-modifying therapeutic effect and ensures that the pivotal trial is well powered to demonstrate efficacy. We will continue to have frequent and consistent interactions with the FDA.

在 A 部分中，影片由多位獨立審閱者使用關鍵試驗方案中的里程碑定義進行集中評級，以確保對發育平台期人群的里程碑獲得和恢復進行客觀、一致的評估，因為預計這些獲得不會自發發生。透過遵循基於自然史的嚴格里程碑評估標準，這種方法最大限度地減少了偏見，並確保里程碑真正有資格獲得或重新獲得，避免了里程碑的過度計數。因此，這能夠可靠地反映 TSHA-102 的疾病改善治療效果，並確保關鍵性試驗有足夠的統計效力來證明其療效。我們將繼續與FDA保持頻繁和持續的互動。

We presented our REVEAL Part A data from the May 2025 data cutoff, including the new supplemental analysis, which provides supportive evidence that further reinforced TSHA-102's consistent, multidomain impact on activities of daily living at the Child Neurology Society Annual Meeting in October. Suku will discuss these results shortly.

我們在 10 月舉行的兒童神經病學會年會上展示了 2025 年 5 月數據截止時的 REVEAL A 部分數據，包括新的補充分析，該分析提供了支持性證據，進一步強化了 TSHA-102 對日常生活活動的持續、多領域影響。Suku稍後將討論這些結果。

With the strength of our Part A clinical data and a clear FDA-aligned path to potential registration, we believe we are strongly positioned to initiate our REVEAL pivotal trial and accelerate execution towards BLA submission. Dosing of the first patient in our REVEAL pivotal trial is scheduled and on track for this quarter, with additional patient enrollment expected to continue across multiple sites this quarter.

憑藉我們強大的 A 部分臨床數據和與 FDA 明確一致的潛在註冊路徑，我們相信我們已做好充分準備啟動 REVEAL 關鍵性試驗，並加快 BLA 提交的執行速度。我們 REVEAL 關鍵性試驗的首例患者給藥計畫已定，並按計畫於本季度進行，預計本季將在多個試驗點繼續招募更多患者。

On the heels of our strong clinical and regulatory progress, we are thrilled to have regained full global rights to our TSHA-102 Rett syndrome program. We regained these rights in October following the expiration of our 2022 option agreement with Astellas, which had granted Astellas an exclusive option to enter into a negotiation period to license TSHA-102 and certain rights with respect to change in control transactions. We appreciate the collaborative relationship we've had with Astellas and the unencumbered rights to TSHA-102 that we now hold enable us to focus on driving long-term value with full strategic flexibility and optionality.

繼我們在臨床和監管方面取得的顯著進展之後，我們非常高興地重新獲得了 TSHA-102 Rett 綜合徵計畫的全部全球權利。2022 年，我們與安斯泰來製藥簽訂的選擇權協議到期，我們在 10 月重新獲得了這些權利。該協議授予安斯泰來製藥獨家選擇權，使其可以進入談判期，以許可 TSHA-102 以及與控制權變更交易相關的某些權利。我們珍惜與安斯泰來製藥的合作關係，我們現在擁有的TSHA-102不受任何限制的權利使我們能夠專注於創造長期價值，並擁有充分的戰略靈活性和選擇權。

We continue to build out our infrastructure to support advancing TSHA-102 toward late-stage development and potential commercialization, if approved. This September, we strengthened our commercial leadership team with the appointment of David McNinch as Taysha's Chief Commercial Officer. David brings over two decades of experience in global commercialization and strategic market development across multiple therapeutic areas.

我們將繼續完善基礎設施，以支援 TSHA-102 進入後期開發階段，並在獲得批准後實現潛在的商業化。今年九月，我們任命 David McNinch 為 Taysha 的首席商務官，加強了我們的商業領導團隊。David 在多個治療領域擁有超過二十年的全球商業化和策略市場開發經驗。

Most recently, he served as Chief Business Officer at Encoded Therapeutics, where he led the commercial and partnering strategy across the company's gene therapy portfolio. He previously held senior commercial roles at Prothena as well as InterMune, where he led the launch of Esbriet, the first FDA-approved treatment for idiopathic pulmonary fibrosis, and supported the company's acquisition by Roche. David reports to Sean McAuliffe, Taysha's Chief Business Officer. Previously at AveXis, Sean led the development and execution of the commercial launch of Zolgensma for spinal muscular atrophy, the first FDA-approved gene therapy for the treatment of a monogenic CNS disease, which has reached blockbuster status.

最近，他曾擔任 Encoded Therapeutics 的首席商務官，負責領導公司基因療法產品組合的商業和合作策略。他之前曾在 Prothena 和 InterMune 擔任高級商業職務，領導推出了 Esbriet，這是首個獲得 FDA 批准的特發性肺纖維化治療藥物，並支持了該公司被羅氏收購。David 向 Taysha 的首席商務長 Sean McAuliffe 報告工作。先前在 AveXis 公司，Sean 領導了用於治療脊髓性肌肉萎縮症的 Zolgensma 的商業化上市開發和執行工作。 Zolgensma 是第一個獲得 FDA 批准用於治療單基因中樞神經系統疾病的基因療法，並已成為重磅藥物。

ith an estimated 15,000 to 20,000 patients with Rett syndrome across the US, EU, and UK, compelling clinical data from Part A of our REVEAL trials, and a minimally invasive, commercially advantageous delivery approach, we see a significant opportunity to address a profound unmet medical need and drive long-term value.

據估計，美國、歐盟和英國有 15,000 至 20,000 名雷特綜合徵患者，我們 REVEAL 試驗 A 部分提供了令人信服的臨床數據，並且我們採用了一種微創、具有商業優勢的給藥方法，因此我們看到了一個解決尚未滿足的重大醫療需求並創造長期價值的巨大機會。

We believe our strong balance sheet, team with proven gene therapy experience, and the clear path to registration strongly position us to initiate our REVEAL pivotal trial and accelerate execution toward BLA submission.

我們相信，我們強大的資產負債表、擁有成熟基因治療經驗的團隊以及清晰的註冊路徑，使我們能夠有力地啟動 REVEAL 關鍵性試驗，並加快 BLA 提交的進程。

I will now turn the call over to Suku to discuss our clinical progress in more detail. Suku?

現在我將把電話交給 Suku，讓他更詳細地討論我們的臨床進展。好嗎？

Thank you, Sean. As Sean mentioned, the regulatory progress we've achieved to date was enabled by the strength of our REVEAL Part A data and our natural history data analysis that allows us to objectively measure developmental milestone gain and regain in the developmental plateau population using each patient as their own control. At the Child Neurology Society Annual Meeting in October, we presented a comprehensive review of our Part A data set using the evaluation frame point and endpoints of our pivotal trial.

謝謝你，肖恩。正如肖恩所提到的，我們迄今為止取得的監管進展得益於我們強大的 REVEAL A 部分數據和自然史數據分析，這使我們能夠客觀地衡量發育停滯人群的發育里程碑的獲得和恢復，並將每位患者作為其自身的對照。在 10 月舉行的兒童神經病學會年會上，我們使用關鍵試驗的評估框架點和終點，對我們的 A 部分數據集進行了全面回顧。

As previously reported, 100% of the 10 patients in Part A achieved one or more natural history-defined developmental milestones following treatment with TSHA-102, with a consistent pattern of early gains that are sustained and new achievements continuing to emerge over time following TSHA-102 treatment. These milestones were all video evidenced and assessed by independent central raters according to the definition of milestone achievement from our pivotal trial protocol.

如先前報導，A 部分的 10 名患者中有 100% 在接受 TSHA-102 治療後達到了一項或多項自然史定義的發育里程碑，早期取得的進步模式得以維持，並且在接受 TSHA-102 治療後，隨著時間的推移，新的成就不斷湧現。這些里程碑事件均有視訊證據，並由獨立的中心評分員根據我們關鍵試驗方案中里程碑事件達成的定義進行評估。

These criteria enabled a reliable, objective, and consistent assessment of TSHA-102's efficacy, and importantly, show that our pivotal trial is well powered to establish the therapeutic impact of TSHA-102. Additionally, we presented a new supplemental analysis of REVEAL Part A data that captured supportive evidence of additional skill gains and improvements outside of the 28 natural history-defined milestones. These gains are derived from the adapted Mullen Scales of Early Learning, the Revised Motor Behavior Assessment or RMBA, and the observer reported communication ability assessment, which are Rett-validated, structured assessments that evaluated prespecified skills and quantifiable improvements.

這些標準能夠對 TSHA-102 的療效進行可靠、客觀和一致的評估，更重要的是，表明我們的關鍵性試驗具有足夠的統計效力來確定 TSHA-102 的治療效果。此外，我們還對 REVEAL A 部分數據進行了新的補充分析，該分析收集了 28 個自然歷史定義的里程碑之外的額外技能提升和改進的支持性證據。這些成果源自於改良的 Mullen 早期學習量表、修訂版運動行為評估 (RMBA) 以及觀察者報告的溝通能力評估，這些都是經過 Rett 驗證的結構化評估，用於評估預先指定的技能和可量化的改進。

The results show that in addition to the developmental milestones achieved across the treatment cohort in Part A, patients consistently gained multiple additional skills and improvements in core disease characteristics across the domains of autonomic function, communication, fine motor, and gross motor areas. We believe these findings reinforce the consistent, broad therapeutic impact of TSHA-102 on activities of daily living that are important to caregivers and clinicians.

結果顯示，除了 A 部分治療組所取得的發展里程碑外，患者在自主神經功能、溝通、精細運動和粗大運動等領域的核心疾病特徵方面也持續獲得了多項額外技能和改善。我們相信這些發現進一步證實了 TSHA-102 對日常生活活動具有持續、廣泛的治療作用，這對護理人員和臨床醫生來說非常重要。

As we continue to prioritize safety, I am pleased to share that TSHA-102 continues to be generally well tolerated, with no treatment-related serious adverse events or dose-limiting toxicities across the 12 pediatric, adolescent, and adult patients treated with the high and low doses of TSHA-102 in Part A of our REVEAL trials as of the October 2025 data cutoff. We are encouraged by the data we've collected from Part A of our REVEAL trials, which we believe support the potential of TSHA-102 to provide meaningful benefit to children, adolescents, and adults living with Rett syndrome. We look forward to reporting longer-term Part A clinical data in the first half of 2026.

在我們繼續將安全性放在首位的同時，我很高興地宣布，截至 2025 年 10 月數據截止日期，在我們的 REVEAL 試驗 A 部分中，接受高劑量和低劑量 TSHA-102 治療的 12 名兒科、青少年和成人患者中，TSHA-102 的耐受性總體良好，沒有發生與限制性治療相關的嚴重毒性事件。我們從 REVEAL 試驗 A 部分收集到的數據令人鼓舞，我們相信這些數據支持 TSHA-102 有可能為患有雷特氏症的兒童、青少年和成人帶來有意義的益處。我們期待在 2026 年上半年公佈更長期的 A 部分臨床數據。

I will now turn the call over to Kamran to discuss financials. Kamran?

現在我將把電話交給卡姆蘭，讓他討論財務問題。卡姆蘭？

Thank you, Suku. Research and development expenses were $25.7 million for the three months ended September 30, 2025, compared to $14.9 million for the three months ended September 30, 2024. The increase was driven by BLA-enabling process performance qualification, or PPQ, manufacturing initiatives, REVEAL clinical trial activities, and higher compensation expenses as a result of increased headcount during the three months ended September 30, 2025. General and administrative expenses were $8.3 million for the three months ended September 30, 2025, compared to $7.9 million for the three months ended September 30, 2024. The increase of $0.4 million was primarily due to debt issuance costs incurred in connection with the refinancing of our existing loan and security agreement with Trinity Capital that are recorded in general and administrative expense under the fair value option and was partially offset by lower legal and professional fees.

謝謝你，Suku。截至 2025 年 9 月 30 日止三個月，研發費用為 2,570 萬美元，截至 2024 年 9 月 30 日止三個月，研發費用為 1,490 萬美元。成長的驅動因素包括：生物製品許可申請 (BLA) 流程表現驗證 (PPQ) 生產計劃、REVEAL 臨床試驗活動，以及截至 2025 年 9 月 30 日的三個月內因人員增加而導致的更高薪資支出。截至 2025 年 9 月 30 日止三個月的行政及一般費用為 830 萬美元，而截至 2024 年 9 月 30 日止三個月的行政及一般費用為 790 萬美元。增加的 0.4 百萬美元主要是由於與我們現有貸款和與 Trinity Capital 的擔保協議進行再融資相關的債務發行成本，這些成本根據公允價值選擇權計入一般及行政費用，部分被較低的法律和專業費用所抵消。

Net loss for the three months ended September 30, 2025, was $32.7 million, or $0.09 per share, compared to a net loss of $25.5 million, or $0.10 per share, for the three months ended September 30, 2024. As of September 30, 2025, Taysha had $297.3 million in cash and cash equivalents. We expect that our current cash resources will support planned operating expenses and capital requirements into 2028.

截至 2025 年 9 月 30 日止三個月，淨虧損為 3,270 萬美元，即每股虧損 0.09 美元，而截至 2024 年 9 月 30 日止三個月，淨虧損為 2,550 萬美元，即每股虧損 0.10 美元。截至 2025 年 9 月 30 日，Taysha 擁有 2.973 億美元的現金及現金等價物。我們預計目前的現金資源將足以支持計畫內的營運支出和資本需求，直到 2028 年。

I will now turn the call over to Sean for his closing remarks. Sean?

現在我將把電話交給肖恩，請他作總結發言。肖恩？

Thank you, Kamran. With Breakthrough Therapy designation and finalized FDA alignment, together with our strong balance sheet and full strategic control of TSHA-102, we believe we are entering the pivotal phase of development with focus and confidence in our ability to redefine the treatment landscape for Rett syndrome while driving long-term value. We remain on track to dose the first patient in our REVEAL pivotal trial with additional enrollment expected at multiple sites this quarter. Additionally, we expect to report longer-term clinical data from Part A of our REVEAL Phase 1/2 trials in the first half of 2026. We look forward to providing further updates as we initiate our REVEAL pivotal trial and advance TSHA-102 towards BLA submission.

謝謝你，卡姆蘭。憑藉突破性療法認定和與 FDA 的最終合作，以及我們強大的資產負債表和對 TSHA-102 的完全戰略控制，我們相信我們正在進入關鍵的研發階段，我們有信心和專注力重新定義雷特綜合徵的治療格局，同時創造長期價值。我們仍按計劃推進 REVEAL 關鍵性試驗的首例患者給藥，預計本季將在多個試驗點招募更多患者。此外，我們預計將於 2026 年上半年公佈 REVEAL 1/2 期試驗 A 部分的長期臨床數據。我們期待在啟動 REVEAL 關鍵性試驗並推進 TSHA-102 向 BLA 提交申請的過程中，提供更多最新資訊。

I will now ask the operator to begin our Q&A session. Operator?

現在我將請接線生開始我們的問答環節。操作員？

(Operator Instructions) Kristen Kluska, Cantor.

（操作員說明）Kristen Kluska，Cantor。

Just curious, this time around in the pivotal trial, you have a lot more evidence going for you. So can you talk about the pipeline of interest and demand for being in this trial and then your thoughts about how long it could take to fully enroll?

我只是好奇，這次在關鍵性審判中，你們有更多的證據對你們有利。那麼，您能否談談目前人們對這項試驗的興趣和需求，以及您認為完全招募參與者可能需要多長時間？

Sure, Kristen. Thanks for the question. I would say unequivocally that the demand to be in the trial is exceptionally high. I think the fact that we've been relatively consistently putting out both safety and efficacy data as we have maturation occur in the study and keeping close contact with the advocacy group, centers of excellence, and KOLS has led to a strong demand.

當然可以，克里斯汀。謝謝你的提問。我可以毫不含糊地說，參與審判的人數非常多。我認為，隨著研究的進行，我們一直相對持續地發布安全性和有效性數據，並與倡導團體、卓越中心和 KOLS 保持密切聯繫，這導致了強烈的需求。

So with that as a backdrop, let me just turn it over to Suku to give a little bit more flavor and then maybe just give timeline parameters around when we expect enrollment could potentially take.

鑑於以上背景，接下來就請 Suku 為大家詳細介紹一下，並給出我們預計招生可能進行的大致時間範圍。

Thanks for that question, Kristen. So as Sean highlighted, we have multiple sites, more than 15 sites identified for our clinical trials program Part B. All of these sites are at centers of excellence. And very interestingly, many of these sites have 100-plus patients per site who have the diagnosis of Rett syndrome. And many of these patients could qualify for a Part B trial. And this includes pediatric, adolescent, and adult patients who will be part of the process.

謝謝你的提問，克里斯汀。正如肖恩所強調的那樣，我們有多個試驗點，超過15個試驗點，用於我們的B部分臨床試驗項目。所有這些試驗點都位於卓越中心。非常有趣的是，這些地點中許多都有 100 多名被診斷出患有雷特氏症的患者。這些患者中有很多可能符合 B 部分試驗的條件。這其中包括兒科、青少年和成年患者，他們都將參與這個過程。

Now furthermore, let me highlight that in the best-case scenario, we could potentially enroll and recruit all 15 patients within a three-month time period, and a more conservative timeline could be between three to six months. And as I said, many of these sites already have multiple patients identified. And there's significant interest in our gene therapy program due to the efficacy already and safety already disclosed in the Part A trial and the ease of route of administration that we have to deliver a gene therapy that already shows significant clinical impact. Thank you.

此外，我想強調的是，在最好的情況下，我們有可能在三個月內招募到全部 15 名患者，而更保守的時間表可能是三到六個月。正如我所說，這些地點中許多地點已經確定有多名患者。由於 A 部分試驗中已揭露的療效和安全性，以及我們採用的簡單給藥途徑，我們的基因治療計畫引起了人們的極大興趣，該基因治療已顯示出顯著的臨床效果。謝謝。

Yeah. And maybe just one more thing to add. We highlighted it in the press release. But to Suku's point, we've got dosing schedules for the first patients already scheduled this quarter, and we expect other patients to enroll at multiple sites this quarter as well. So I think that speaks to both the demand and the alacrity at which the sites have worked to initiate the pivotal trial.

是的。或許還有一點需要補充。我們在新聞稿中重點強調了這一點。但正如 Suku 所說，我們已經安排了本季首批患者的給藥方案，我們預計本季也會有其他患者在多個地點入組。所以我認為這不僅體現了需求，也體現了各試驗點為啟動這項關鍵性試驗所採取的迅速行動。

And Kristen, one more point I should emphasize is many of these sites may be able to dose more than one patient in a staggered parallel fashion. So we might be able to get one, two, or three patients to, three weeks apart at some of these sites, which would further accelerate our timelines and hopefully make the submission of the BLA timeline even shorter and make this product available to deserving patients who have Rett syndrome.

克里斯汀，我還要強調一點，這些場所中的許多場所可能能夠以交錯並行的方式給予多個患者。因此，我們或許可以在其中一些試驗點，每隔三週安排一到三名患者接受試驗，這將進一步加快我們的進度，並有望縮短生物製品許可申請 (BLA) 的提交時間，使患有雷特綜合徵的合格患者能夠獲得該產品。

Salveen Richter, Goldman Sachs.

薩爾文·里克特，高盛。

I was just wondering if you could touch on expectations for the longer-term data in the first half of next year and also help us understand in the context of your discussions with the FDA what they have signed off on in terms of that minimum threshold for success here that's sufficient for filing.

我想請您談談對明年上半年長期數據的預期，並幫助我們了解在您與FDA的討論背景下，他們批准了哪些最低成功門檻，這些門檻足以提交申請。

Thanks for the question, Salveen. For the first part of the question, relative to what updates will we give in the first half of next year, I think it'll be consistent with what you've seen. As the data matures, we've tried to look at things as a full cohort. So ultimately, we want to get to, we have all 12 patients at 12 months, and I think that'll be very important data to look at relative to the six-month time point, where are we at 12 months with these patients. And so we'll do that.

謝謝你的提問，薩爾文。關於問題的第一部分，即明年上半年我們將發布哪些更新，我認為這將與你們所看到的保持一致。隨著數據的成熟，我們嘗試從整體角度來看問題。所以最終，我們希望能夠獲得所有 12 名患者 12 個月的追蹤數據，我認為這將是非常重要的數據，可以相對於 6 個月的時間點進行觀察，看看這些患者在 12 個月時的情況如何。所以我們會這麼做。

In addition to that, I think it's important to continue to provide updates relative to the safety profile. So we want a little bit of flexibility here that we could potentially give an update in the first quarter with almost 12 months of data, we could do -- we could wait for the second quarter, but we want to -- we just want to make sure that the market is aware of the fact that we do plan to give further updates both in terms of safety and efficacy that we think will be very enlightening and informative relative to the predictability of the approval of the pivotal trial. So that's number one.

除此之外，我認為繼續提供有關安全狀況的最新資訊也很重要。所以我們希望在這裡留有一些靈活性，我們可以在第一季度發布更新，屆時將有近 12 個月的數據；我們也可以等到第二季度，但我們想確保市場了解，我們計劃就安全性和有效性方面提供進一步的更新，我們認為這些更新對於預測關鍵性試驗的批准將非常有啟發性和信息量。這是第一點。

Number two, as it relates to FDA alignment, we highlighted in the script and I think it's really important that back in September the FDA put out guidance that's very consistent with everything we've done to date in our interactions with them, which is very specifically, they want alignment on your SAP before you start your clinical trial. Like that is the highly recommended path to take.

第二點，關於與 FDA 的協調，我們在腳本中重點強調了這一點，我認為這一點非常重要：FDA 在 9 月發布的指導意見與我們迄今為止與他們互動所做的一切都非常一致，具體來說，他們希望在開始臨床試驗之前與你的 SAP 達成一致。這正是我們強烈推薦的做法。

And that's exactly what we've done. We submitted the SAP going back as far as January. When we got the okay to go ahead and submit the final SAP and the clinical protocol by the end of the second quarter without an end-of-phase meeting, we did that. We've answered all the then subsequent queries from the statistical analysis plan question and clinical questions. And we actually even reached out to the FDA because we had believed we'd answered all their questions, and we sent them a note and said, we just want to confirm that there's no other outstanding statistical or clinical questions. And they said, confirmed.

而我們也正是這樣做的。我們提交的 SAP 資料最早可以追溯到一月。當我們獲得批准，可以在第二季末提交最終的 SAP 和臨床方案，而無需召開階段結束會議時，我們就這樣做了。我們已經回答了統計分析計劃問題和臨床問題之後的所有後續問題。我們甚至聯繫了 FDA，因為我們認為我們已經回答了他們所有的問題，我們給他們發了一份說明，說，我們只是想確認是否還有其他未解決的統計或臨床問題。他們說，確認了。

So we feel everything that we've just presented with the [NF15], the threshold of a responder being the gain or regain of one milestone and crossing the threshold of having a 33% response rate, all ties to the statistical plan that we've submitted.

因此，我們認為我們剛才提出的 [NF15] 的所有內容，即應答者的門檻是獲得或重新獲得一個里程碑，以及超過 33% 的應答率門檻，都與我們提交的統計計劃有關。

So we feel we're very much in alignment with the FDA. And the other thing I would just note is that per the FDA's internal SOPs, these milestone meetings where you're talking about the final protocol, the SAP internally, the Directors are at those meetings. So I can't give you specific names who are there, but that is the protocol. So we feel, again, supremely confident at this particular point in time. We've done everything that this FDA has asked us to do.

因此，我們感覺我們與FDA的立場非常一致。我還要指出一點，根據 FDA 的內部標準作業規程，在這些里程碑會議上，也就是討論最終方案的會議上，內部標準作業程序 (SAP) 的負責人都會參加。所以我不能告訴你具體有哪些人在那裡，但這是規定。因此，我們再次感到無比自信。我們已經按照美國食品藥物管理局（FDA）的要求做了所有事情。

We've been in full alignment with them the entire way. And I would argue, we were in full alignment with the Peter Marks regime as well. And I think that's all because of the integrity of the data and the quality and rigor of the data collection that we've put forward. So we think we've checked all the boxes, we've double checked, and we're told we're good to go. And that's why it's full steam ahead on patient enrollment right now.

我們始終與他們保持一致。而且我認為，我們當時也完全與彼得馬克斯政權保持一致。我認為這完全是因為資料的完整性以及我們提出的資料收集方法的品質和嚴謹性。所以我們認為我們已經檢查了所有事項，我們反覆確認過，並被告知一切就緒。所以，目前我們正全力推動病患招募工作。

Tazeen Ahmad, Bank of America.

塔津·艾哈邁德，美國銀行。

I wanted to get a little bit more color on how you're thinking about the way we should all be thinking about the data from the younger patients, meaning the two- to six-year-olds, relative to the six-plus-year-olds as it relates to efficacy in particular.

我想更詳細地了解您是如何看待我們所有人應該如何看待年輕患者（即 2 至 6 歲兒童）的數據，特別是與 6 歲及以上兒童的數據在療效方面的差異。

And then on safety, should we be expecting to see a staggered release of safety data on that younger population relative to the older population? Basically, when could we expect to see data start to come in from that cohort base?

那麼，關於安全性，我們是否應該預期看到針對年輕族群的安全資料與針對老年族群的安全資料分階段發布？基本上，我們什麼時候才能開始看到來自該隊列的數據？

Yeah, sure. Thanks for the questions, Tazeen. Number one, I think the headline is our goal is to ensure that by the time we submit the BLA under any circumstance that these two- to five-year-old population is included in that, okay, so that we would have a very broad two-plus label effectively. And so the way we're stepping through that is this quarter, we'll be having dialog with the FDA. We've submitted the protocol to them, so we'll be getting some feedback on that. It is a safety focused study.

當然可以。謝謝你的提問，塔津。首先，我認為重點是我們的目標是確保在任何情況下，當我們提交生物製品許可申請時，2 至 5 歲人群都被納入其中，這樣我們就能有效地擁有一個非常廣泛的「兩歲以上」標籤。因此，我們解決這個問題的方法是，本季我們將與FDA進行對話。我們已經將方案提交給他們了，所以我們會收到一些回饋意見。這是一項以安全為重點的研究。

We have had discussions with the FDA, formal meetings with the FDA, where we've basically made the following request, that for this population, we want to establish safety, number one. We will collect some efficacy data, of course, but what we proposed was that we could extrapolate efficacy from the six-plus population and that that would be sufficient for getting this younger group into the label. And the FDA agreed to that. So that's how we're going to step through it. We would anticipate beginning to dose these patients once we have alignment with the FDA, probably towards the middle of 2026.

我們已經與 FDA 進行了討論，與 FDA 舉行了正式會議，我們基本上提出了以下要求，那就是對於這一群體，我們希望首先確保安全性。我們當然會收集一些療效數據，但我們提出的方案是，我們可以從六歲以上人群的療效數據推斷出療效，這足以讓這個更年輕的群體獲得該標籤。美國食品藥物管理局也同意了這一點。所以，這就是我們要一步一步來的方法。我們預計在與 FDA 達成協議後，即可開始給這些患者用藥，大概在 2026 年年中。

Again, because it's safety, we think the trains will align on time in terms of BLA submissions, and then we'll follow efficacy over the course of time in this patient population to see if there's things that are unique there. And if appropriate, we could certainly update the label with any new data we have. But again, to just restate the primary goal is that, at approval you would have a label of two-plus with no specific constraints relative to efficacy that's been collected. It's the full population that you're getting approval on.

再次強調，因為這是安全問題，我們認為生物製品許可申請的提交會按時完成，然後我們會長期追蹤​​該患者群體的療效，看看是否有任何獨特之處。如果合適，我們當然可以根據我們掌握的新數據更新標籤。但再次重申，主要目標是，在獲得批准時，您將獲得一個「2+」的標籤，並且沒有與已收集的功效相關的任何具體限制。你獲得的是全體人口的批准。

Gil Blum, Needham & Company.

吉爾布魯姆，尼德姆公司。

So maybe just another one on protocols here. How much leeway do you think the agency provides regarding the method of video review and is it fair to assume that all companies in the space receive the same guidance on that?

所以，這裡可能又是另一個關於協議的問題。您認為該機構在影片審查方法上給予了多大的自由裁量權？是否可以合理地假設該領域的所有公司都得到了相同的指導？

Yeah, Gil, I would say in our experience, the most time we spent in dialog with the FDA was around the rigor of the data collection for the primary endpoint. They were very much focused on how we were going to do that, that there was high fidelity in the data, and that there was high inter-rater reliability. And in fact, what we did to further bolster our case with the FDA is we actually ran a pilot at multiple sites testing the DMA with multiple central raters, and we submitted that as part of our data package to get the protocol approved and also in the Breakthrough Therapy package as well.

是的，吉爾，根據我們的經驗，我們與 FDA 對話花費的時間最多，主要圍繞主要終點資料收集的嚴謹性。他們非常關注我們將如何做到這一點，確保數據的準確性，以及評分者之間的信度。事實上，為了進一步加強我們向 FDA 提交的申請，我們實際上在多個地點進行了試點，使用多個中心評級員測試了 DMA，並將此作為數據包的一部分提交，以獲得方案批准，同時也將其納入了突破性療法包中。

And so all I can say is that like anything, you're as good -- in our space, you're as good as the data that you're collecting. FDA was super focused on that. So I'm assuming anyone going into a pivotal trial would be held to the standard of a minimum of video evidence and having it centrally adjudicated. I think the question is have you run the experiment, and do you know that the methodology you're employing is going to give you the result that you anticipate. And what we feel good about is we've run that result.

所以我只能說，就像任何事情一樣，你的水平——在我們這個領域，你的水平取決於你收集的數據的品質。FDA對此非常關注。因此，我認為任何進入關鍵審判程序的人都將受到最低限度的視頻證據要求，並由中央進行裁決。我認為問題在於你是否已經進行了實驗，以及你是否確信你所採用的方法可以得到你預期的結果。我們感到欣慰的是，我們得到了這樣的結果。

We've collected the data from our Part A study, and we've done central raters with that. But then the pilot study, which you really haven't talked too much about, but we ran that in the background again at multiple sites, and that gives us the confidence, and hopefully gave the FDA confidence that what we're putting forward is highly rigorous, high-end fidelity, and high-end inter-rater reliability.

我們已經收集了 A 部分研究的數據，並進行了中心評分。但是，您並沒有過多提及的試點研究，我們在多個地點再次進行了後台運行，這讓我們有信心，也希望讓 FDA 有信心，我們提出的方案具有高度的嚴謹性、高保真度和高評分者間信度。

Biren Amin, Piper Sandler.

比倫·阿明，派珀·桑德勒。

This is [Michael] on for Biren. Are there any updates on your plans in Europe or discussions with the EMA on the applicability of Part B? And separately, is the bar for the interim analysis similar to that for the final 12-month analysis?

這是麥可代表比倫上場。關於您在歐洲的計劃或與歐洲藥品管理局 (EMA) 就 B 部分適用性進行的討論，是否有任何最新進展？另外，中期分析的標準是否與最終 12 個月分析的標準相似？

Thanks, Michael. Thanks for the question. First and foremost, our focus has been and will be on the US, number one, two, and three. That's the biggest market out there. We've been historically resource constrained, both financially as well as human resource capital wise.

謝謝你，麥可。謝謝你的提問。首先，我們的重點一直是並將繼續是美國，排名第一、第二和第三。那是最大的市場。我們在歷史上一直面臨資源限制，包括資金和人力資源的資源。

We're in a better position now, but we've really worked to make sure that we are as aligned as possible, with the highest probability possible to get things approved as safely and as quickly as we can in the US. We will continue, and what we've been doing, Michael, with Europe and the UK is working to enable them, so stepping through regulatory dialogs and things of that nature. We think that as we further generate data in Part A and also get into Part B, that will further inform those discussions and will give us even clearer line of sight to what the options we have. We know we're going to have multiple options to go into Europe.

我們現在的情況好多了，但我們確實努力確保我們盡可能保持一致，以盡可能安全、盡可能快速地在美國獲得批准。我們將繼續努力，邁克爾，我們一直在與歐洲和英國合作，為他們創造條件，例如透過監管對話等方式。我們認為，隨著我們在 A 部分進一步生成數據，並進入 B 部分，這將進一步為這些討論提供信息，並使我們更清楚地了解我們有哪些選擇。我們知道我們將有多種方式進入歐洲。

There's some that we've taken in the past that would be the most efficient and make the most sense for all parties involved. We want to see if we can work to enable that. The other thing, too, is from a policy perspective, I think, we all know the challenges on both sides of the pond. We want to make sure we focus here at home and lock in those things. And we can also take the time while we're collecting the data to see how policy also shakes out from an ex-US perspective as well. So the long-term goal is to enable Europe for sure. It's just a question of stepping through it in a very thoughtful manner.

我們過去採取的一些措施，對於所有相關方來說，都是最有效率、最合理的。我們想看看能否透過努力實現這一點。另外，從政策角度來看，我認為我們都知道大西洋兩岸面臨的挑戰。我們希望確保在家中集中精力，把這些事情做好。我們也可以利用收集資料的時間，從美國以外的角度來看政策的最終結果。因此，長遠目標是確保歐洲的繁榮發展。這只是需要一步一步、深思熟慮地去完成的問題。

Maury Raycroft, Jefferies.

莫里‧雷克羅夫特，傑富瑞。

Congrats on the progress. Wondering if you'd tell us anything additional about timelines for IRB approval for the additional two to five sites that you'll need for the pivotal. And just when thinking about enrollment for this study, is there anything more you could say about number of patients you could potentially have enrolled by end of this year? Just helping provide some line of sight to potentially getting to data from the pivotal by the end of next year.

恭喜你取得進展。想請您告知我們關於關鍵性試驗所需的另外兩到五個研究中心的 IRB 批准時間表方面的其他資訊。考慮到這項研究的招募工作，您能否透露到今年底可能招募到的患者人數？只是幫助大家了解一下，是否有可能在明年年底前獲得關鍵數據。

Yeah, Maury, it's a great question. I think we can provide more information in either Q1 or sometime in the springtime, I think, as we have better line of sight. Again, just from how we're stepping through it, we've submitted protocol to the FDA, we've got a -- waiting for their feedback on that. That'll certainly inform things. We're doing -- I would say, contextually, we're doing for the pivotal trial, 15 patients. This is a smaller subset of patients. So we would anticipate the number of patients to be less than 15 in this study.

是的，莫里，這是一個很好的問題。我認為我們可以在第一季或春季的某個時候提供更多信息，因為那時我們對情況會有更清晰的了解。再說一遍，就我們目前的進展來看，我們已經向FDA提交了方案，現在正在等待他們的回饋。這肯定會對事情有所啟發。我們正在進行中——我想說，就關鍵性試驗而言，我們正在招募 15 名患者。這是一小部分患者。因此，我們預計這項研究中的患者人數將少於 15 人。

I think that from a IRB perspective, it will be a new protocol. So it'll have to go through the process of contracting IRB approval, ethics, all the things that you have to do. I can tell you that there are, as you would anticipate, multiple sites, of course, that want to be a part of this.

我認為從倫理審查委員會的角度來看，這將是一項新的協議。所以它必須經過合約審批、倫理審查等所有必須做的事情。我可以告訴你，正如你所預料的那樣，當然有很多網站都想參與其中。

So I don't think that's going to be an issue. We just want to make sure that, number one, we get alignment first and foremost with the FDA on the protocol and the associated statistical plan that we're putting forward. And then number two, that from an operational perspective, we're doing things in a manner that is most efficient and doesn't by any way impede the enrollment of the six-plus population.

所以我覺得這應該不會是個問題。我們首先要確保的是，我們與 FDA 在方案和相關統計計劃方面達成一致。第二點，從營運角度來看，我們做事的方式是最有效率的，而且絕對不會以任何方式阻礙六歲以上人群的入學。

So the way we see this, based on the fact that the primary endpoint in the little kids study, is safety -- we think the two trains are going to come back together. And again, just to make the point that we do anticipate including that data along with the six-plus pivotal data in the BLA submission with the goal of getting a broad label.

所以，根據小朋友研究的主要終點是安全這一事實，我們認為這兩列火車最終會重新匯合。再次強調，我們預計將這些數據與六個以上的關鍵數據一起納入 BLA 申請中，目標是獲得廣泛的適應症標籤。

Jack Allen, Baird.

傑克艾倫，貝爾德。

Congrats on all the progress made over the course of the quarter. I guess my first one was on the broader sentiment of the FDA. There was quite a bit of news over the weekend and Monday morning driving CBER and some changes outside CDER. And I just wanted to get a sense for any thoughts that the team has as it relates to management interactions with the agency, whether the agency is functioning as expected and what your plans are going forward to interact.

恭喜你們在本季取得的所有進展。我想我的第一個問題是針對FDA的整體看法。週末和週一早上有很多關於 CBER 和 CDER 外部變化的新聞。我只是想了解團隊對於管理層與代理商的互動有什麼想法，代理商是否按預期運作，以及你們未來有什麼互動計劃。

And then briefly on the younger patient cohort, I also wanted to ask about how you're thinking about dose. As you go into younger patients, you could theoretically increase the relative exposure if you're treating smaller patients with a fixed dose. I'm just curious if you have any plans to address that potential issue.

然後，關於年輕患者群體，我還想簡單問一下您是如何考慮劑量問題的。對於年齡較小的患者，如果使用固定劑量治療體型較小的患者，理論上可以增加相對暴露量。我只是好奇你們是否有計劃解決這個潛在問題。

Yeah, Jack, let me start with the second part of your question on dose. It's going to be 1x10 15 total vg, but we're going to adjust for brain volume. So we want to make sure that none of those younger kids get any more dose on a per-kilogram basis than anyone we've dosed so far safely. So we've given that a lot of thought. The clin dev team has done a super job.

好的，傑克，讓我先回答你關於劑量問題的第二部分。總共是 1x10 15 vg，但我們會根據腦容量進行調整。所以我們希望確保這些年齡較小的孩子每公斤體重所接受的劑量不會超過我們迄今為止安全用藥的任何人的劑量。所以我們對此進行了深入思考。臨床開發團隊做得非常出色。

Again, we've got that in front of the FDA. So we're being very thoughtful about that safety perspective. So more to come on that once we have the protocol finalized. As it relates to the FDA, what we can point to is a couple of things. And I said this earlier.

我們已經把這個問題提交給FDA了。所以，我們在安全方面考慮得非常周全。等協議最終確定後，我們會發布更多相關資訊。關於美國食品藥物管理局（FDA），我們可以指出兩點。我之前也說過。

We had good alignment with Nicole Verdun. Nothing that we've changed -- we've done nothing since the new regime's been in that's different in terms of our natural history assessment, our proposed endpoints, et cetera. And I've used this term before, but no one has pushed us off the ball. And the reason we believe that is because we have levered data collected in a very rigorous manner to make our case with the FDA. Number two, the approach that we're taking is exactly what the FDA wants.

我們與妮可·凡爾登的合作非常順利。我們沒有做出任何改變——自從新政權上台以來，我們在自然史評估、提議終點等方面沒有任何變化。我以前也用過這個詞，但沒有人把我們從球上推開。我們相信這一點的原因是，我們利用以非常嚴謹的方式收集的數據來向 FDA 證明我們的觀點。第二，我們採取的方法正是 FDA 所希望的。

So that's why we referenced this FDA guidance from September where they're basically saying, hey, for gene and cell therapies, we want alignment on your protocol and your SAP before you start the study. So what are we doing? We've taken our first-in-human study. We've learned from that. We've done the natural history analysis.

所以，這就是為什麼我們引用了 FDA 9 月發布的這份指南，其中他們基本上是說，嘿，對於基因和細胞療法，我們希望在你們開始研究之前，在方案和 SAP 上達成一致。所以我們現在在做什麼？我們已經完成了首次人體試驗。我們從中吸取了教訓。我們已經完成了自然史分析。

And now what we're saying is, based on what we've learned, we're going to propose a prospective pivotal trial with the following endpoint and the following statistical analysis plan. And we've worked with the FDA to get that into a situation where they've signed off on that. So we've done exactly what they wanted. Our understanding is any of these milestone meetings like signing off on a protocol or Breakthrough designation, which I can talk about in a second.

現在，根據我們所了解的情況，我們將提出一項前瞻性關鍵性試驗，其終點如下，統計分析計劃如下。我們已經與美國食品藥物管理局 (FDA) 合作，最終獲得了他們的批准。所以我們已經完全照他們的要求做了。我們理解，這些里程碑式的會議包括簽署協議或突破性療法認定等，我稍後會詳細討論。

But internally, the Directors are in those meetings. So we've checked and double-checked to make sure we're not misinterpreting things. We've gotten confirmation of that. We feel like we've done everything that the FDA has asked us to do. And more importantly, we're not asking them to do something that's out of course. What we're not doing is we're not taking the Part A data and saying, oh, you know what, we want you guys to go back and we're going to propose now that we're doing a DMA, and we're going to do these developmental milestones. So we want you to approve our data based on a statistical plan we put in front of you after the fact.

但就公司內部而言，董事們都會參加這些會議。所以我們已經反覆核查，以確保我們沒有誤解任何事情。我們已經得到證實。我們感覺我們已經按照FDA的要求做了所有事情。更重要的是，我們並沒有要求他們做任何超出他們能力範圍的事情。我們不做的是，我們不會拿 A 部分的數據說，哦，你知道嗎，我們希望你們回去，我們現在要提議進行 DMA，我們要進行這些發展里程碑。所以我們希望您根據我們事後向您提供的統計方案來批准我們的數據。

That is not something that we've done. We're taking a more traditional approach and starting a new study. Suku, want to add some information?

我們沒有做過那樣的事。我們將採取更傳統的方式，進行一項新的研究。Suku，你想補充一些資訊嗎？

Yeah, one thing I would add, Sean, is that under Dr. Vinay Prasad and Vijay Kumar's current leadership of CBER, they have -- their team has followed the spirit of the RMAT designation in CBER and the Breakthrough designation that we have achieved. So our interactions have been very fluid and very constructive and very useful. So I just wanted to emphasize that.

是的，肖恩，我還要補充一點，在維奈·普拉薩德博士和維傑·庫馬爾目前領導的CBER中，他們的團隊一直秉承著CBER的RMAT認證精神和我們所取得的突破性認證。因此，我們的互動非常流暢、非常有建設性，也非常有益。所以我只是想強調這一點。

Yeah, I mean, Jack, one last thing on Breakthrough to the point Suku is making. The internal SOP at FDA for Breakthrough is that when a Breakthrough request comes in, the Directors are made aware of it. They then send it to the review team and assign them to review it and let them know the recommendation. And so that means that eyes are on things. And again, we've done the best that we can to be data driven in all of our requests.

是的，我是說，傑克，關於Suku提出的突破性觀點，我還有最後一點要補充。FDA 內部關於突破性療法申請的標準操作程序是，當收到突破性療法申請時，主管人員會被告知。然後他們將其發送給審核團隊，並指派他們進行審核，並將建議告知審核團隊。所以這意味著大家都在關注著事情。再次強調，我們已盡最大努力在所有請求中都做到數據驅動。

And therefore, again, we feel the fact that the Breakthrough was granted in September under this current regime in the manner that they like. We've followed their guidance that they've issued in September in terms of protocol for pivotals as well as SAP. We've tried to step through it in exact manner that they want and, I would argue, the exact manner based on data that any administration would want. So that's why I went back into the Wayback Machine with the Peter Marks' group. But it is important, and I do think it's relevant, to say they agreed with what we were doing as well, based on the way that we were going through it.

因此，我們再次感到，突破性進展是在現任政府的領導下，以他們喜歡的方式於 9 月獲得的。我們一直遵循他們在 9 月發布的關於關鍵環節和 SAP 協議的指導方針。我們已經盡力按照他們想要的方式一步一步地完成這項工作，而且我認為，這也是任何一屆政府都會希望採用的基於數據的方式。所以，這就是我和彼得馬克斯的團隊一起回到網路檔案館的原因。但我認為，他們也認同我們的做法，這一點很重要，而且也很有意義，因為我們處理事情的方式與他們一致。

So I've always said data drives -- is the currency of the realm. And we believe that's the case. We're just going to keep moving forward and be as transparent as we can with the agency. And as a result of having Breakthrough, we now can set up even additional meetings with them, which we've already done, to start to talk about BLA submission process and things of that nature.

所以我一直都說，數據驅動——是這個領域的貨幣。我們相信情況確​​實如此。我們將繼續前進，並盡可能對相關機構保持透明。由於有了 Breakthrough，我們現在可以與他們安排更多會議（我們已經這樣做了），開始討論 BLA 提交流程以及類似的事情。

Chris Raymond, Raymond James.

克里斯·雷蒙德，雷蒙德·詹姆斯。

Just a couple of commercial questions here maybe. So you're starting the commercial buildout now with the hiring of a Chief Commercial Officer. Maybe talk about the footprint you'll need, how it will look, and maybe the milestones that we should expect in terms of, I guess, access progress.

這裡可能就幾個商業問題。所以你們現在開始著手商業建設，首先要聘請一位首席商務官。或許可以談談你需要的佔地面積、它的外觀，以及在接觸進度方面我們應該期待的里程碑。

And then maybe a related question. Of the 28 developmental milestones, are there any that you think matter more, be it communication, fine motor, or gross motor milestones in terms of clinical acceptance among the physician community, or in terms of ease of access that we should be thinking about?

然後或許還會有一個相關的問題。在 28 個發展里程碑中，您認為有哪些里程碑在臨床上更容易被醫生群體接受，或者在易於獲取方面，是溝通、精細運動還是粗大運動方面的里程碑，值得我們考慮？

Yeah. I think to start with your second question, all of the 28 milestones that we selected, we did in concert with KOLs and with the advocacy community. So if you were talking to some of the KOLs, they would talk about higher order milestones. So there's 51 milestones, Chris, in the natural history database. You'll hear like that language, because these are the milestones that, from a clinical and from a functional perspective, really do matter across the three different domains.

是的。我認為，先回答你的第二個問題，我們選擇的這 28 個里程碑都是與 KOL 和倡議團體共同製定的。所以，如果你和一些KOL（關鍵意見領袖）交談，他們會談論更高層次的里程碑。克里斯，自然史資料庫中共有 51 個里程碑。你會聽到這樣的措辭，因為從臨床和功能角度來看，這些里程碑在三個不同的領域中確實非常重要。

So I wouldn't say anyone rises to the level more than anyone else. It's all relevant to the particular situation of each individual patient. I will say that when you talk to the parents communication is top of mind with them. They want to know what hurts, what do they want, are they hungry, how can they make them feel better, those kinds of things, which make a lot of sense. But that's why we feel we've reached that agreement with the FDA that any 1 of those 28 is relevant.

所以，我不會說有人比其他人優秀。這一切都與每位患者的具體情況有關。我想說的是，當你和家長交談時，溝通是他們最關心的問題。他們想知道哪裡痛，想要什麼，餓不餓，怎麼樣才能讓他們感覺好些，諸如此類的問題，都很有道理。但正因如此，我們才覺得我們已經與 FDA 達成一致，即這 28 項中的任何一項都具有相關性。

And I think what we're also trying to show is that over time, not only are there more milestones being gained of the 28, but the whole purpose of the supplemental analysis was to show that outside of that -- the 28 are a mechanism for us to get approval, but outside of that, in multiple scales, whether it be done from the clinicians or rated independently like the Mullen or the ORCA, which is the parents and what they're saying that they're noticing. The point of that was to say, beyond the 28 that we've talked about, there's a lot of other things happening that are great.

我認為我們還要表明的是，隨著時間的推移，不僅在 28 項指標中取得了更多里程碑式的進展，而且補充分析的全部目的在於表明，除了這 28 項指標之外——這 28 項指標是我們獲得批准的機制，除此之外，在多種尺度上，無論是臨床醫生進行的評估，還是像 Mullen 或 ORCA 這樣的獨立評估，也就是父母所觀察到父母的評估。我的意思是，除了我們討論過的 28 件大事之外，還有很多其他很棒的事情正在發生。

And we're seeing good things. The parents are seeing things. The clinicians are seeing improvements in function, and all of that is going to be what we put forward to the FDA in the final package and would also be part of what we discuss with payers. Suku?

我們看到了一些好的改變。父母想太多了。臨床醫生發現患者的功能有所改善，所有這些都將是我們最終提交給 FDA 的材料，也將是我們與支付方討​​論的內容之一。好嗎？

Yeah, thanks, Sean. And one more thing I would add is that -- Chris, is that as our trial design is patient as their own control, every milestone matters. So it doesn't matter what the milestone is out of the 28, to the patient, to the parent, or the caregiver, all of them actually matter, and all of them have impact on activities of daily living. And given our Part A data set, my hope as a physician and clinician is that there will be no patient left behind over time as we gather more data from Part B.

謝謝你，肖恩。我還要補充一點——克里斯，由於我們的試驗設計是讓患者本身作為對照，所以每個里程碑都很重要。所以，對於病人、家長或照顧者來說，28 個里程碑中的哪一個並不重要，所有里程碑其實都很重要，而且所有里程碑都會對日常生活活動產生影響。鑑於我們 A 部分的數據集，作為一名醫生和臨床醫生，我希望隨著我們從 B 部分收集更多數據，不會有病人被落下。

Yeah. And then the first part of your question, Chris, about commercial, I'd say a couple things. First, you're definitely on the leading edge of the curve here. We think starting in the first quarter, we really are going to put more color around how we see the commercial opportunity. I think, for starters, it really is underappreciated how large the patient population is. So we're doing a lot of work relative to claims data analysis and things of that nature to put finer points on things.

是的。至於你問題的第一部分，克里斯，關於商業方面，我想說幾點。首先，你絕對處於這個領域的前沿。我們認為從第一季開始，我們將更詳細地闡述我們對商業機會的看法。我認為，首先，人們真的低估了患者群體的龐大規模。因此，我們正在進行大量與理賠數據分析以及類似性質的工作，以完善細節。

We're also looking at the launch of Daybue. That's going to be a good surrogate for potential uptake. And the more that we're digging into things, the more robust we think the opportunity truly is, particularly in a situation where the data set that we're going to be able to discuss with payers and also get the treating clinicians and the families hopefully excited about what they're seeing is that no one's been able to demonstrate functional gains before in a neurodevelopmental disease, even in adults. So that opens up a really significant opportunity.

我們也在關注Daybue的發布。這將是一個很好的衡量潛在接受度的指標。我們越深入研究，就越覺得這個機會非常可觀，尤其是在我們能夠與支付方討​​論數據集，並希望能夠讓治療臨床醫生和患者家屬對他們所看到的情況感到興奮的情況下，因為此前沒有人能夠在神經發育疾病中證明功能性改善，即使是在成年人中也是如此。這便帶來了一個非常重要的機會。

And we also have known from the get-go that using CGI and RSBQ and those type of scales is going to mean absolutely nothing to the payers. They do not care what a CGI score actually is. They want to know what they're paying for. And what they're going to be paying for is going to be improvements in function or gains of function that haven't been demonstrated, which is why we feel so strongly that this endpoint for a gene therapy is the right way to go.

而且我們從一開始就知道，使用 CGI 和 RSBQ 以及這類量表對支付者來說根本沒有任何意義。他們根本不在乎CGI評分到底是什麼。他們想知道他們付的錢都花在哪裡了。他們最終要支付的費用，實際上是尚未得到證實的功能改善或功能提升，因此我們堅信，基因療法的這一終點是正確的方向。

An example is in Canada, the HTA denied Daybue being reimbursed because they couldn't determine the clinical relevance of a 0.3 change in CGI. So again, I think we're going to be on really strong ground with the data set that we're putting forward in a very significant patient population. And the other thing I'll say just in terms of the team, David McNinch is our new Chief Commercial Officer. He's got a ton of experience. He and I work together at InterMune on the launch of Esbriet, which was a big success.

例如，在加拿大，衛生技術評估機構拒絕為 Daybue 提供報銷，因為他們無法確定 CGI 變化 0.3 的臨床意義。所以，我認為我們提出的這組數據來自一個非常重要的患者群體，所以我們會有非常堅實的基礎。另外，關於團隊方面，我要說的是，David McNinch 是我們新的首席商務官。他經驗非常豐富。我和他一起在 InterMune 工作，共同推出了 Esbriet，並取得了巨大的成功。

David was also recently at Encoded. He knows gene therapy very well. He reports to Sean McAuliffe, who's our Chief Business Officer. Sean was on the Zolgensma launch team. So we've got a very stacked group internally and, I would say, on the Medical Affairs team, our Head of Medical Affairs, Alain, ran Med Affairs in Canada for Acadia.

David 最近也參加了 Encoded 的活動。他對基因療法非常了解。他向首席商務官肖恩·麥考利夫匯報工作。Sean 是 Zolgensma 上市團隊的成員。所以我們內部有一個非常強大的團隊，而且，我想說的是，在醫療事務團隊中，我們的醫療事務主管 Alain 曾負責 Acadia 在加拿大的醫療事務。

So we feel like the field team and the commercial team, call it, the external-facing group, we've got just a stellar all-star team, and we'll continue to put out more perspective on that as we generate the data and move towards the BLA submission. Great question.

因此，我們感覺我們的現場團隊和商業團隊（或對外團隊）都是一支非常優秀的明星團隊，隨著我們收集數據並向生物製品許可申請 (BLA) 提交申請，我們將繼續就此發表更多看法。問得好。

Yanan Zhu, Wells Fargo Securities.

朱亞楠，富國證券。

Wanted to dig into the statistical plan a little bit. Thanks for all the color so far on the call regarding alignment and the FDA. Given that the trial design is novel and there is not an external control arm, per se, wonder how the p-value is derived. And also in terms of the interim analysis, how unambiguous or subjective the threshold is for triggering filing based on interim? In other words, do you run any risk if you file on interim? Just wondering with regard to the actual data and the p-value in making that decision.

想稍微深入研究一下統計方案。感謝各位在電話會議中就對齊和FDA相關問題提供的所有資訊。鑑於該試驗設計新穎，且本身沒有外部對照組，我想知道 p 值是如何得出的。此外，就中期分析而言，根據中期分析觸發申報的門檻是明確還是主觀？換句話說，如果您提交中期報告，是否會面臨任何風險？我只是想知道在做出這個決定時，實際數據和 p 值的情況。

So that's a good question. I'll try to answer that for you in very simple, straightforward terms. So the evaluations are not subjective, they're actually quite objective, because remember, we have a natural history that is very tightly analyzed and the FDA accepted our natural history analysis. But it's very clear once these patients get above six years of age, they do not gain new milestones, or they do not regain milestones. And our evaluation process for achievement of new milestones or regain of milestones is video recorded.

這是個好問題。我會盡量用最簡單明了的語言來回答你的問題。所以這些評估不是主觀的，實際上相當客觀，因為記住，我們對自然史進行了非常嚴格的分析，而且FDA接受了我們的自然史分析。但很明顯，一旦這些患者超過六歲，他們就不會再取得新的發展里程碑，或不會再恢復先前的發展里程碑。我們對新里程碑的達成或重新取得里程碑的評估過程會進行錄影。

And as Sean has pointed out earlier, it's very rigorously evaluated by blinded central reviewers. And there are different reviewers for the six-month interim analysis as well as the 12-month interim analysis. So you have to keep that in mind as well. Now remember, also the six-month interim analysis, all 15 patients dosed have to reach that six-month time point before we break the blind on the video evaluations and before we share the information or the data with the FDA for potentially filing on the BLA as we complete the study at 12 months. And that data set will also be available at the final filing of the BLA.

正如肖恩之前指出的那樣，它是由匿名中央評審員進行非常嚴格的評估的。六個月中期分析和十二個月中期分析的審閱者是不同的。所以你也要記住這一點。現在請記住，還有六個月的中期分析，所有 15 名接受治療的患者都必須達到六個月的時間點，我們才能在視頻評估中揭盲，才能與 FDA 分享信息或數據，以便在 12 個月的研究完成後可能提交 BLA 申請。該資料集也將在生物製品許可申請最終提交時提供。

So what we do is by the six-month interim analysis process, we have the opportunity to shorten the timeline of filing of the BLA by two quarters more. So again, the six-month interim analysis also does not really have significant impact on the p-value nor the power of the study, given that the loss of the alpha is actually minimal, and it's a 33% responder rate is all that's needed really to meet our primary endpoint, whether it's a 6-month or 12-month analysis. And keep in mind that usually none of these patients at six months reach a new milestone or regain a lost milestone. Therefore, any milestone gained even by one patient is miraculous. So I will leave it at that.

因此，透過六個月的中期分析流程，我們有機會將生物製品許可申請 (BLA) 的提交時間再縮短兩個季度。因此，六個月的中期分析對 p 值或研究效力也沒有真正的重大影響，因為 alpha 的損失實際上很小，而且 33% 的回應率就足以達到我們的主要終點，無論是 6 個月還是 12 個月的分析。請記住，通常情況下，這些患者在六個月時都不會達到新的里程碑，也不會重新獲得失去的里程碑。因此，即使只有一個病人取得進步，也是個奇蹟。我就說到這裡吧。

From a clinician's perspective, I think we have something that I hope that we can gather the data quickly and get our data set to the FDA so that we can make this therapy available to patients as soon as possible. I hope that answers your question, Yanan.

從臨床醫生的角度來看，我認為我們有一些希望，希望我們能夠盡快收集數據並將我們的數據集提交給 FDA，以便我們能夠盡快為患者提供這種療法。希望這能解答你的疑問，亞南。

Joon Lee, Truist Securities.

Joon Lee，Truist Securities。

This is Mehdi on for Joon. So the question is, I just wanted to ask you to please remind us what is the actual definition of regaining again. And assuming that at the six-month interim data is positive, how soon you can start filing for BLA?

這是 Mehdi 為 Joon 做客。所以問題是，我只是想請您提醒我們一下，「重新獲得」的真正定義是什麼。假設六個月的中期數據顯示結果為陽性，那麼多久可以開始申請生物製品許可申請 (BLA)？

Yeah, thanks for that question. So this is Suku, and I'll respond to that question because it's -- thanks because it's important that it's clearly defined and the audience understands what it means. So remember again, natural history, once patients with Rett syndrome reach the age of six and above, they do not regain a lost milestone.

謝謝你的提問。所以這裡是 Suku，我會回答這個問題，因為──謝謝，因為明確定義它很重要，觀眾也要理解它的意義。所以再次記住，根據自然病程，雷特症候群患者一旦達到六歲以上，他們就不會再恢復失去的發育里程碑。

So I'll give you an obvious one. Let's assume a patient before six years of age with Rett syndrome can sit up without support and they lose it completely and now cannot sit up without support. Post treatment with TSHA-102, our gene therapy through lumbar puncture, if that patient now again is able to sit without support, that is a regain of a lost milestone.

那我就給你舉個顯而易見的例子吧。假設一名患有雷特氏症的兒童在六歲之前可以不用支撐就能坐起來，但後來完全喪失了這種能力，現在無法不用支撐就能坐起來。接受 TSHA-102（我們的基因療法，透過腰椎穿刺）治療後，如果該患者能夠再次無需支撐地坐起來，那就是重新獲得了失去的一個里程碑。

A gain of a new milestone is something where the patient before the age of six, for example, can never use their fingers due to significant stereotactic movements and therefore, cannot pick up a teaspoon or a cup to feed themselves. Post treatment, this milestone is now achieved where the patient can actually use their fingers, which they've never done before, can pick up a spoon or a cup and feed themselves. That is the gain of a new milestone. So it's very almost black and white, which actually makes it very easy both for the clinicians who are evaluating the patients, the video reviewers who are blinded, as well as when the FDA hopefully sees our videos, it will make it obvious that our product actually works.

取得新的里程碑式進展是指，例如，六歲前的患者由於嚴重的立體定位運動而永遠無法使用手指，因此無法拿起茶匙或杯子來自己吃飯。治療後，患者現在已經達到了一個里程碑式的進步，他現在可以真正使用自己的手指，這是他以前從未做到的，他可以拿起湯匙或杯子自己吃飯。這是取得的一個新里程碑。所以情況幾乎是黑白分明的，這實際上讓評估患者的臨床醫生、不知情的視頻審查員以及 FDA（希望如此）在看到我們的視頻時都很容易看出我們的產品確實有效。

And keep in mind that this entire process of video recording, central raters, blinding, et cetera, came from our AveXis experience many years ago. And we have most of the team here at Taysha that will continue to execute on this program and hopefully reproduce what we were able to do for SMA population using AVXS-101, which is now Zolgensma.

請記住，錄影、中央評分員、盲法等整個過程都源於我們多年前在 AveXis 的經驗。我們泰莎團隊的大部分成員將繼續執行該計劃，並希望能夠重現我們使用 AVXS-101（現為 Zolgensma）為 SMA 患者所取得的成就。

It appears we have no further questions at this time. I'll turn the program back to the speakers for any additional or closing remarks.

目前看來我們沒有其他問題了。我將把發言權交還給發言者，讓他們補充或作總結發言。

We appreciate everyone taking the time this morning to join us. Have a good day. Thank you.

感謝大家今天上午抽出時間參加我們的活動。祝你有美好的一天。謝謝。

This concludes today's program. Thank you for your participation, and you may disconnect at any time.

今天的節目到此結束。感謝您的參與，您可以隨時斷開連線。